Wu Xiao-Hui, Wang Jun-Ming, Qin Ling-Yu, Zhang Tian-Zhu, Li Ya-Min, Zhang Yue-Yue, Long Bing-Yu, He Qing-Wen, Ji Li-Jie, Song Ling-Ling
School of Pharmacy,Henan University of Chinese Medicine Zhengzhou 450046,China.
School of Pharmacy,Henan University of Chinese Medicine Zhengzhou 450046,China Collaborative Innovation Center for Respiratory Disease Diagnosis and Treatment & Chinese Medicine Development of Henan Province,Henan University of Chinese Medicine Zhengzhou 450046, China.
Zhongguo Zhong Yao Za Zhi. 2023 Oct;48(19):5326-5336. doi: 10.19540/j.cnki.cjcmm.20220710.701.
For the first time, this study evaluated the gender differences and mechanisms of the antidepressant effects of raw Rehmanniae Radix(RRR) based on the classic depression model with traditional Chinese medicine syndrome of Yin deficiency and internal heat. The depression model with Yin deficiency and internal heat was established by the widely recognized and applied method of thyroxine induction of the classic depression model with Yin deficiency and internal heat(chronic unpredictable mild stress). Male and female mice were simultaneously treated with RRR. The study analyzed indicators of nourishing Yin and clearing heat, conventional antidepressant efficacy test indicators, and important biomolecules reflecting the pathogenesis and prevention and treatment mechanisms of depression, and conducted a correlation analysis of antidepressant efficacy, Yin-nourishing and heat-clearing efficacy, and biological mechanism in different genders, thereby comprehensively assessing the antidepressant effects of RRR on depression of Yin deficiency and internal heat, as well as its gender differences and mechanisms. RRR exhibited antidepressant effects in both male and female mouse models, and its antidepressant efficacy showed gender differences, with a superior effect observed in females. Moreover, the effects of RRR on enhancing or improving hippocampal neuronal pathology, nucleus-positive areas, postsynaptic dense area protein 95, and synaptophysin protein expression were more significant in females than in males. In addition, RRR significantly reversed the abnormal upregulation of nuclear factor(NF)-κB/cyclooxygenase 2(COX2)/NOD-like receptor thermal protein domain associated protein 3(NLRP3) pathway proteins in the hippocampus of both male and female mouse models. The antidepressant effects of RRR were more pronounced in depression female mice with Yin deficiency and internal heat syndrome, possibly due to the improvement of neuronal damage and enhancement of neuroplasticity. The antidepressant mechanisms of RRR for depression with Yin deficiency and internal heat syndrome may be associated with the downregulation of the NF-κB/COX2/NLRP3 pathway to reduce neuronal damage and enhance neuroplasticity.
本研究首次基于中医阴虚内热证经典抑郁模型，评估了生地黄（RRR）抗抑郁作用的性别差异及机制。采用公认且应用广泛的甲状腺素诱导经典阴虚内热抑郁模型（慢性不可预测温和应激）的方法，建立阴虚内热抑郁模型。对雄性和雌性小鼠同时给予RRR进行处理。本研究分析了滋阴清热指标、常规抗抑郁药效学试验指标以及反映抑郁症发病机制和防治机制的重要生物分子，并对不同性别小鼠的抗抑郁药效、滋阴清热药效与生物学机制进行相关性分析，从而全面评估RRR对阴虚内热型抑郁症的抗抑郁作用及其性别差异和机制。RRR在雄性和雌性小鼠模型中均表现出抗抑郁作用，且其抗抑郁药效存在性别差异，雌性小鼠效果更佳。此外，RRR对增强或改善海马神经元病理、细胞核阳性面积、突触后致密区蛋白95和突触素蛋白表达的作用，雌性小鼠比雄性小鼠更显著。另外，RRR显著逆转了雄性和雌性小鼠模型海马中核因子（NF）-κB/环氧化酶2（COX2）/NOD样受体热蛋白结构域相关蛋白3（NLRP3）通路蛋白的异常上调。RRR对阴虚内热型抑郁雌性小鼠的抗抑郁作用更为明显，这可能是由于其改善了神经元损伤并增强了神经可塑性。RRR对阴虚内热型抑郁症的抗抑郁机制可能与下调NF-κB/COX2/NLRP3通路以减少神经元损伤和增强神经可塑性有关。
